This invention relates to methods for the controlled handling and storage of unstable proteins or other molecules and the improved production, filling, and storage of dry forms of such molecules.
Many useful proteins and other molecules that are unstable in aqueous solutions are handled and stored in a dry powder form. Bulk drying and lyophilization (freeze-drying) are known, useful ways to stabilize protein structure and activity. Traditional freeze-drying methods involve the freezing of an aqueous solution containing various stabilizing agents, followed by application of a vacuum to remove the water by sublimation, producing a dry powder that is relatively stable and suitable for long-term storage. Lyophilization, such as in the manufacture of a variety of pharmaceutical products, typically is conducted by filling a vessel, such as vial or ampule, with an aqueous solution of the product pharmaceutical, and then placing the vial in a refrigerated tray within a lyophilizer. Optionally the filled vial is first frozen in a separate chamber before being placed into the lyophilizer. Actual practice demands that many vials are placed within an aseptic lyophilizer for simultaneous processing. Lyophilization, however, can be difficult to optimize, particularly with vial-to-vial uniformity. Processing difficulties include determining what process conditions (i.e. cycle) to use, and then ensuring that each vial experiences exactly the same processing conditions. One of the primary sources of these problems is heat transfer, which is difficult to achieve in a vacuum—such as the vacuum chamber of the lyophilizer. It would be advantageous to improve the heat transfer in lyophilization processes.
In some cases, lyophilization is better than drying protein formulations, because it avoids exposing the formulation to capillary forces associated with evaporation from a liquid to a gas phase. In other cases, however, the damage to proteins from lyophilization, caused by freezing and sublimation, may exceed the damage due to evaporation, and a drying technique thus may be preferable. Nevertheless, evaporation from bulk solutions is generally slow and formulation components often degrade during the drying process as they are concentrated in the solution. It would be advantageous to provide methods for preparing stable, dry powder forms of proteins and other molecules that reduce the disadvantages associated with bulk drying and/or lyophilization.
Powder filling technologies, however, are not as well developed as liquid filling methods, and the amount of powder deposited in a particular container can be difficult to measure and control. For example, dry powders frequently are sensitive to packing forces, static charge, moisture, and other variables that can affect the handling of the powder. Such variables can make it difficult to reproduce or deliver precise quantities, particularly microquantities, of the powders. It therefore would be advantageous to provide methods for improving the accuracy of handling precise quantities of dry powders.
It therefore would be desirable to provide improved methods for obtaining stable, dry powder forms of proteins and other molecules. In addition, it would be desirable to provide methods for delivering precise quantities of dry proteins and other molecules to preselected sites. It would also be desirable to provide microscale reservoirs containing a pharmaceutical formulation that will be stable over long periods.